Diabetes - Long term complications

Question 1

What is the most common cause of death in diabetic patients?

Answer 1

People with diabetes have a mortality rate over twice that of age matched controls. Cardiovascular disease accounts for 70% of all deaths. Atherosclerosis in diabetic patients occurs earlier and is more extensive. Diabetes amplifies the effects of other cardiovascular risk factors: smoking, hypertension, and dyslipidaemia.

Question 2

What is diabetic microangiopathy?

Answer 2

Disease affecting the small blood vessels, is a specific complication of diabetes. It damages the kidneys, the retina and the peripheral and autonomic nerves causing substantial morbidity and disability: blindness, difficulty walking, chronic foot ulceration, and bowel and bladder dysfunction. The risk of microangiopathy is related to the duration and degree of hyperglycaemia. One of the most consistent morphological features of diabetes is diffuse thickening of the basement membrane. The basal lamina separating parenchymal or endothelial cells from the surrounding tissue is thickening by layers of hyaline material.

Of note, despite an increase in the thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins.

Question 3

How can diabetic complications be prevented?

Answer 3

Several trials have shown that improved glycaemic control decreases the risk of microvascular complications in diabetes.

The DCCT study showed that strict glycaemic control reduces complications but with a much higher risk of hypoglycaemia in type 1 patients. The UKPDS showed that in type 2 patients, the frequency of diabetic complications is lower and progression is slower with good glycaemic control and effective treatment of hypertension, irrespective of the type of therapy used. For every 11 mmol/ mol (1%) reduction in HbA1c there is a 21% reduction in deaths related to diabetes, a 14% reduction in MI and 30-40% reduction in microvascular complications.

Question 4

How should HbA1c be lowered in elderly patients compared with younger ones?

Answer 4

The DCCT and UKPDS trials have shown that diabetic complications are preventable and that the aim of treatment should be “near-normal” glycaemia. However, the ACCRD study showed increased mortality in a high risk sub group of patients who were treated aggressively to lower their HbA1c to <48 mmol/mol (6.5%). Therefore, whilst a low target HbA1c is appropriate in younger patients with earlier diabetes without underlying cardiovascular risk factors, aggressive glucose lowering is not beneficial for elderly patients with a long duration of diabetes and multiple comorbidities.

Question 5

What is the pathogenesis of diabetic retinopathy?

Answer 5

DR is a common cause of blindness in adults. Hyperglycaemia increases retinal blood flow and metabolism, and has direct effects on retinal endothelial cells, resulting in impaired vascular autoregulation. This leads to chronic tissue hypoxia, which stimulates production of growth factors and causes new vessel formation and increased vascular permeability.

Question 6

What are the major risk factors for diabetic retinopathy?

Answer 6

Long duration of diabetes
Poor glycaemic control
Hypertension
Hyperlipidaemia
Pregnancy
Nephropathy/ renal disease
Others: obesity, smoking

Question 7

Where are the complications of diabetes most commonly found?

Answer 7

In most patients, morphologic changes are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy) and other tissues. These changes are seen in both type 1 and type 2 disease.

Question 8

How is diabetic retinopathy classified?

Answer 8

The current classification of diabetic retinopathy comes from the Early Treatment Diabetic Retinopathy Study (ETDRS), and comprises:

• non proliferative diabetic retinopathy (NPDR), mild, moderate and severe
• proliferative diabetic retinopathy (PDR)
• diabetic maculopathy

Question 9

What is non proliferative diabetic retinopathy?

Answer 9

Non proliferative diabetic retinopathy includes a spectrum of changes resulting from structural abnormalities of retinal vessels (specifically post capillary venules) that are confined beneath the internal limiting membrane of the retina. The basement membrane of the blood vessels is thickened.

NPDR is typified by microaneurysms, dot haemorrhages and hard yellow exudates with well defined edges (called background retinopathy in some classifications).

Question 10

Can NPDR affect a patients vision?

Answer 10

The changes in NPDR do not have any effect on vision if they occur in the peripheral retina. However, there is a spectrum of changes in NPDR, some of which are associated with more ischaemic damage. These changes were previously classified as “pre-proliferative” retinopathy. The features of this more ischaemic moderate to severe NPDR are:

i) intraretinal microvascular abnormalities (IRMA)
ii) cotton wool spots
iii) deeper blotch and cluster haemorrhages
iv) venous dilation, beading and looping

NPDR may coexist with diabetic maculopathy. The more ischaemic NPDR changes should alert the clinician to the possibility of progression to blinding proliferative diabetic retinopathy.

Question 11

What is the appearance of microaneurysms in diabetic eye disease?

Answer 11

These are tiny, discrete red dots near to retinal vessels. They are the earliest abnormality detected in diabetic eye disease. They are narrower than the vessels at the disc margin.

Question 12

How do haemorrhages appear?

Answer 12

Haemorrhages are larger than microaneurysms, have less clear margins and are wider than the vessels at the disc margin. Superficial flame shaped haemorrhages in the nerve fibre layer also occur, particularly in hypertensive patients.

Question 13

What do hard exudates appear as?

Answer 13

Hard exudates are yellow, irregular lesions, sometimes is a circular pattern formed from leaking cholesterol. They are associated with retinal oedema. If they occur in the macula they can cause clinically significant macular oedema (CSMO).

Question 14

Describe the appearance of cottonwool spots

Answer 14

Unlike hard exudates, these are white fluffy lesions seen in rapidly advancing retinopathy or with uncontrolled hypertension. They are a marker of more ischaemic changes in NPDR.

Question 15

How does venous beading appear?

Answer 15

This can be subtle, but appears are saccular bulges in vein walls. Intraretinal microvascular anomalies (IRMA) appear as spidery vessels. Both of which are associated with progressing retinopathy and ischaemic changes in NPDR.

Question 16

What is proliferative diabetic retinopathy? What complications can this be associated with?

Answer 16

This is characterised by the growth of new vessels on the retina or into the vitreous cavity. They are thought to result from the ischaemic diabetic retina producing vasoproliferative factors that cause the growth of abnormal new vessels. These vessels may bleed causing a sudden decrease in vision because of vitreous haemorrhage. Worse still, this blood often results in the production of contractile membranes that gradually pull off the retina (tractional retinal detachment), causing blindness. This may occur in any diabetic patient, but more commonly seen in younger type 1 patients. The vision may be 6/6 right up to the moment of haemorrhage, so early detection of new vessels by adequate fundal examination is crucial. Fluorescein angiography may help identify areas of retinal ischaemia and new vessel formation.

Question 17

What does neovascularisation look like on ophthalmoscopy?

Answer 17

This appears as fine tufts of vessels forming arcades on the retinal surface, later extending forwards on to the vitreous. These new vessels can rupture causing sudden visual loss.

Question 18

How is laser treatment used to treat proliferative diabetic retinopathy?

Answer 18

Laser treatment (or any other method of photocoagulation) is used to treat proliferative retinopathy. The laser, however, is usually not used to coagulate new vessels as they may bleed or recur. When a patient has new vessels at the disc, the entire retina is treated with a laser, except for the macula area, which preserves central vision. This treatment, often called “panretinal photocoagulation” or “pattern bombing” destroys much of the ischaemic peripheral retina and stops it producing vasoproliferative factors that induce the growth of new vessels. New blood vessels on the iris that block the outflow of aqueous and cause rubeotic glaucoma may also regress. However, thousands of laser burns may be needed to achieve this. This treatment may substantially reduce peripheral vision and night vision and means that the patient may have to give up driving.

Question 19

Are there any medical therapies for proliferative diabetic retinopathy?

Answer 19

Yes. Anti-VEGF therapies such as bevaxcizumab and ranibizumab can be used to treat diabetic macular oedema. Currently, both price and frequency of attendance required (both for injections and follow up) limit the use of these in clinical practice. Ranibizumab is currently NOT recommended by NICE for the treatment of visual impairment due to diabetic macular oedema. Intravitreal steroids are also used.

Question 20

What is diabetic maculopathy?

Answer 20

Diabetic maculopathy can be divided into 4 groups:

i) focal exudative macular oedema
ii) diffuse exudative macular oedema
iii) ischaemic maculopathy
iv) mixed types

When diabetic retinopathy causes vessel leakage and ischaemia in the macula area, central vision may be severely affected. Diabetic maculopathy is the major cause of blindness in maturity onset (type 2) diabetes, but it also occurs in younger insulin dependent diabetics. It may be amenable to photo laser coagulation, which may help to reduce any leakage, particularly when hard exudates are a prominent feature of the maculopathy.

Question 21

How can diabetic retinopathy be prevented?

Answer 21

Good glycaemic control reduces the risk of retinopathy. Early diagnosis and treatment is important - in type 2 diabetics 25% present with established retinopathy. However, rapid reduction in blood glucose may cause an initial deterioration in retinopathy by causing relative ischaemia, so glycaemic control should be improved gradually. Control of hypertension is of proven benefit but intervention for hyperlipidaemia is unproven in DR.

Annual screening for retinopathy is essential in all diabetic patients, especially those with risk factors. The preferred method is digital photography.

Question 22

Name some other causes of visual loss in diabetics

Answer 22

Around 50% of visual loss in people with type 2 diabetes is due to causes OTHER than diabetic retinopathy. These include:

• cataract
• macular degeneration
• retinal vein occlusion
• retinal artery occlusion
• ischaemic optic neuropathy
• glaucoma

Cataract occurs prematurely in people with diabetes due to metabolic damage to the lens.

Question 23

Patients who require screening for diabetic retinopathy can be divided into 5 groups. Outline what these are

Answer 23

1) Patients with no retinopathy or with minimal non proliferative (background) retinopathy and normal vision when test with glasses or pinhole - yearly review
2) Patients with non proliferative (background) retinopathy and changes around the macula area - refer to ophthalmologist, as this may point to blinding maculopathy
3) Patients with non proliferative (background) retinopathy and impaired acuity not corrected with glasses. The patient may have an oedematous or ischaemic form of maculopathy that is extremely hard to diagnose
4) Patients with moderate to severe non proliferative retinopathy. They have no new vessels, and there are cottonwool spots. These signs imply that the retina is ischaemic and that there is a high risk that new vessels will form. Refer
5) Patients with proliferative retinopathy. This is typified by new vessel formation, and sometimes cottonwool spots, fibrosis and vitreous haemorrhage. These patients need immediate referral.

Question 24

What are the risk factors for developing diabetic nephropathy?

Answer 24

About 30% of patients with type 1 diabetes have developed diabetic nephropathy after 20 years, but the risk after this time falls to <1%/yr. Risk factors include:

• poor glycaemic control
• duration of diabetes
• other microvascular complications
• ethnicity: Asian, Pima Indians
• hypertension
• family history of nephropathy or hypertension

Question 25

What is the pathology of diabetic nephropathy?

Answer 25

Thickening of the glomerular basement membrane is followed by nodular deposits (Kimmelsteil-Wilson nodules). As glomerulosclerosis worsens, heavy proteinuria develops, sometimes in the nephrotic range, and renal function progressively worsens.

Question 26

How is diabetic nephropathy diagnosed?

Answer 26

Microalbuminuria (defined as a urine ablumin:creatinine ratio of 2.5-30 mg/ mmol creatinine in men, 3.5-30 mg/mmol creatinine in women; undetectable on dipstick) is a risk factor for developing overt diabetic nephropathy, although it is also found in other conditions.

Overt nephropathy is defined as the presence of macroalbuminuria (urinary albumin of >300 mg/day; detectable on urine dipstick). Patients with type 1 diabetes should be screened annually for 5 years after diagnosis; those with type 2 diabetes should be screened annually from the time of diagnosis.

Question 27

How is diabetic nephropathy managed?

Answer 27

Progression of nephropathy can be reduced by improved glycaemic control and aggressive reduction of BP and other cardiovascular risk factors.

In type 1 diabetics, ACEi provide greater protection than equal BP reduction achieved with other drugs. Similar benefits results from angiotensin II receptor blockers (ARBs) in type 2 diabetics. Non dihydropyridine calcium antagonists (e.g. diltiazam, verapamil) may be suitable alternatives.

Halving the amount of albuminuria with an ACEi or ARB reduces the risk of progression to end stage renal disease by nearly 50%. However, in those that do progress, renal replacement therapy is of value at an early stage in diabetes.

Renal transplantation dramatically improves the life of many, and recurrence of diabetic nephropathy in an allograft is rare.

Question 28

What lesions are encountered in diabetic nephropathy?

Answer 28

Three lesions are encountered:

1) glomerular lesions
2) renal vascular lesions, principally arteriosclerosis, and
3) pyelonephritis, including necrotizing papillitis

Question 29

What glomerular lesions are seen in diabetes?

Answer 29

The most important glomerular lesions seen in diabetic nephropathy are capillary basement membrane thickening, diffuse mesangial sclerosis and nodular glomerulosclerosis. The glomerular basement membranes are thickened along their entire length.

Question 30

What is diffuse mesangial sclerosis?

Answer 30

Diffuse mesangial sclerosis consists of a diffuse increase in mesangial matrix along with mesangial cell prolfieration and is always associated with basement membrane thickening. It is found in most individuals with disease of more than 10 years duration. When glomerulosclerosis becomes marked, patients manifest with nephrotic syndrome, characterised by proteinuria, hypoalbuminaemia and oedema.

Question 31

What is nodular glomerulosclerosis?

Answer 31

This describes a glomerular lesion made distinctive by ball-like deposits of a laminated matrix situated in the periphery of the glomerulus. These nodules are PAS positive and usually contain trapped mesangial cells. This distinctive change has been called the Kimmelsteil-Wilson lesion. Nodular glomerulosclerosis is encountered in approximately 15-30% of persons with long term diabetes and is a major contributor to morbidity and mortality.

Diffuse mesangial sclerosis can also be seen in association with old age and hypertension; by contrast, nodular glomerulosclerosis is essentially pathognomonic of diabetes.

Both the diffuse and nodular forms of glomerulosclerosis induce sufficient ischaemia to cause scarring of the kidneys, manifested by a finely granular appearing cortical surface.

Question 32

How are the renal arteries affected by diabetes?

Answer 32

Renal atherosclerosis and arteriosclerosis are part of the microvascular disease seen in diabetes. The kidney is one of the most frequently and severely affected organs. However, the changes in the arteries and arterioles are the same as those seen in other areas throughout the body. Hyaline arteriosclerosis affects not only the afferent but also the efferent arteriole. Such efferent arteriosclerosis is rarely, if ever encountered in a patient who does not have diabetes.

Question 33

What is pyelonephritis?

Answer 33

Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to involve the tubules. Both the acute and chronic forms of this disease occur in nondiabetics as well as in diabetics but are more common in patients with diabetes. Once affected, diabetics tend to have more severe involvement. One special pattern of acute pyelonephritis, called necrotizing papillitis, is much more prevalent in diabetics than nondiabetics.

Question 34

How is the nervous system affected in diabetes?

Answer 34

The central and peripheral nervous system are not spared by diabetes. The most frequent pattern of involvement is that of a peripheral, symmetric neuropathy of the lower extremities affecting both motor and sensory function. Other forms include autonomic neuropathy, which produces disturbances in bowel and bladder function. The neurologic changes may be the result of microangiopathy and increased permeability of capillaries that supply the nerves, as well as direct axonal damage.

Question 35

How common is diabetic neuropathy?

Answer 35

Diabetic neuropathy affects 50-90% of patients. It is symptomless in the majority of cases and can involve motor, sensory and autonomic nerves. Prevalence is related to the duration of diabetes and the degree of metabolic control.

Question 36

What is the most common form of diabetic nephropathy? Describe the clinical features

Answer 36

Symmetric sensory polyneuropathy is the most common, and is quite often asymptomatic. The most common signs are diminished perception of vibration distally, “glove and stocking” impairment of all sensory modalities, and loss of tendon reflexes in the legs.

Symptoms may include paraesthesia in the feet or hands, pain on the anterior aspect of the legs (worse at night), burning sensation in the soles of the feet, hyperaesthesia and a wide based gait. Toes may be clawed with wasting of the interosseous muscles.

A diffuse small fibre neuropathy causes altered pain and temperature sensation and is associated with symptomatic autonomic neuropathy; characteristic features include foot ulcers and Charcot neuroarthropathy.

Question 37

What is diabetic amyotrophy?

Answer 37

This is an asymmetric motor diabetic neuropathy. This presents as severe, progressive weakness and wasting of the proximal muscles of the legs (occasionally arms), accompanied by severe pain, hyperaesthesia and paraesthesia. There may also be marked loss of weight (“neuropathic cachexia”) and absent tendon reflexes. The CSF protein is often raised. This condition is thought to involve acute infarction of the lumbosacral plexus. Although recovery usually occurs within 12 months, some deficits may be permanent.

Question 38

What are the clinical features of a diabetic mononeuropathy?

Answer 38

Either motor or sensory function can be affected within a single or peripheral or cranial nerve. Unlike other neuropathies, mononeuropathy is severe and of rapid onset. The patient usually recovers. Most commonly affected are the 3rd and 6th cranial nerves (causing diplopia) and femoral and sciatic nerves. Multiple nerves are involved in mononeuritis multiplex. Nerve compression palsies commonly affect the median nerve and lateral popliteal nerve (foot drop).

Question 39

What are the important features of autonomic neuropathy associated with diabetes?

Answer 39

This is less clearly related to poor metabolic control, and improved control rarely improves symptoms. Within 10 years of developing autonomic neuropathy, 30-50% of patients are dead. Postural hypotension indicates a poor prognosis.

Question 40

How is the pain and paraesthesia of diabetic peripheral somatic neuropathy treated?

Answer 40

Strict glycaemic control
Anticonvulsants (e.g. gabapentin)
Antidepressants (e.g. amitriptyline, duloxetine)
Substance P depleter (capsaicin - topical)
Opiates (e.g. tramadol , oxycodone)
Membrane stabilisers (eg. mexiletine, IV lidocaine)
Antioxidant (alpha lipoic acid)

Question 41

How is autonomic neuropathy treated?

Answer 41

Symptomatic support can be achieved using the following:
- Postural hypotension: fludrocortisone, NSAIDs, midodrine, compression stockings

• Gastroparesis: metoclopramide, erythromycin, gastric pacemaker, enterostomy feeding
• Motility disorders: (1) diarrhoea = loperamide, octreotide, (2) constipation = stimulant laxatives
• Atonic bladder: intermittent self catheterisation
• Excessive sweating: propantheline, clonidine, topical antimuscarinics (e.g. glycopyrrolate)
• Erectile dysfunction: sildenafil, prostaglandin injections

Question 42

What causes diabetic foot disease?

Answer 42

Tissue necrosis in the feet is a common reason for hospital admission in diabetic patients. Foot ulceration occurs as a result of often trivial trauma in the presence of neuropathy and/ or peripheral vascular disease. Infection often follows this.

Most ulcers are neuropathic or neuroischaemic in type. They usually develop at the site of a plaque of callus skin, beneath which tissue necrosis occurs, eventually breaking through the surface. Charcot neuro-arthropathy, with destructive inflammation of neuropathic joints is usually caused by diabetes. These patients have high arches.

Question 43

How are diabetic feet managed?

Answer 43

Preventative treatment is the most effective method of managing the diabetic foot. Patient education is crucial. Annual screening should include formal testing of sensation and removal of callus. Further management includes:

• debridement of tissues
• prompt and prolonged antibiotics in the presence of infection
• bespoke orthotic footwear
• vascular assessment: angiography/ vascular reconstruction if the foot is ischaemic
• Charcot foot: cast immobilisation, and avoidance of weight bearing
• amputation: if these is extensive tissue/ bony destruction, or intractable ischaemic pain when vascular reconstruction is not possible or has failed